It is generally the case that organic compounds must be synthesized as pure substances through well-planned reactions and scrupulous separation/purification. In fields such as drug discovery, catalyst design and new material development, tens of thousands of organic compounds must be synthesized and tested to discover a few active ones. In the pharmaceutical industry, for example, synthesizing large numbers of compounds in the traditional way is ineffective relative to the rapid emergence of new biological targets. A major factor limiting the productivity of orthodox solution (liquid) phase organic synthesis is the time consuming process of purification. High throughput organic synthesis, therefore, preferably integrates organic reactions with rapid purification/separation procedures.
The attachment of “tags” to organic reaction components has become commonplace in combinatorial and parallel high throughput syntheses to facilitate the separation process. See, for example, Curran, D. P. “Strategy-level Separations in Organic Synthesis; From Planning to Practice,” Angew. Chem., Int. Ed. Eng. 1998, 37, 1175–1196; Flynn, D. “Phase-trafficking Reagents and Phase-switching Strategies for Parallel Synthesis,” Med. Res. Rev. 1999, 19, 408–432. The process of tagging excess reagents, reactants, catalysts or byproducts for their separation from the desired products is often called “scavenging” or “quenching”. In a common embodiment of tagging, a substrate, for example a small organic molecule, is tagged with a separation tag typically comprised of a polymeric bead in a technique known as “solid phase synthesis”. See, for example, Seneci, P. “Solid-phase Synthesis and Combinatorial Technologies,” John Wiley and Sons New York, 2000. Conducting one or more reactions on the tagged substrate (or subsequent intermediates) with untagged reagents, reactants, catalysts, etc. then provides a tagged product. The presence of the separation tag allows easy separation of the tagged intermediates and/or product from untagged reagents, reactants, catalysts and/or products derived therefrom. For example, simple filtration is usually used to separate the polymer bead tagged intermediate or product from solvent, byproduct and/or any unreacted reagent.
Because reactions with polymer-bound substrates and intermediates are typically heterogeneous, large excesses of reagents are often needed to drive reactions to completion. This adds to the expense of a reaction and can also lead to unwanted tagged byproducts. Even when using excesses of reagents, solid phase synthesis methods often do not match their solution phase counterparts in terms of speed, yield, scope and cleanliness of products. Furthermore, other than by filtration, it is not usually possible to further purify polymer-bound intermediates and products. In other words, polymer bound intermediates or products cannot be separated from bound byproducts without removal from the polymer and subsequent purification. Accordingly reactions on the solid phase that occur with broad scope in quantitative yield (so that no polymer-bound byproducts are formed) are the target of much research.
In a common embodiment of scavenging, a solution phase reaction is conducted under standard conditions, and then a scavenger or quencher is added and allowed to react with one or more reaction components that have been targeted for separation from the desired products. The most commonly used scavengers are solid-phase materials such as polymers or bonded phases of silica. See, for example, Kaldor, S. W., Siegel, M. G. “Combinatorial Chemistry Using Polymer Supported Reagents,” Curr. Opin. Chem. Bio. 1997, 1, 101–106; Shuttleworth, S. J., Allin, S. M., Sharma, P. K. “Functionalised Polymers: Recent Developments and New Applications in Synthetic Organic Chemistry,” Synthesis 1997, 1217–1239; Ley, S. V., et al. “Multi-step Organic Synthesis Using Solid-supported Reagents and Scavengers: A New Paradigm in Chemical Library Generation,” J. Chem. Soc., Perkin Trans. 1 2000, 3815–4195; Eames, J., Watkinson, M. “Polymeric Scavenger Reagents in Organic Synthesis,” Eur. J. Org. Chem. 2001, 1213–1224.
Like reactions with polymer-bound substrates, reactions with solid phase scavengers are almost always heterogeneous. Large excesses of solid phase scavengers are often used to facilitate the scavenging reaction, yet the speed and cleanliness of solution phase reactions still often cannot be duplicated. Solution phase scavengers with appropriate acid or basic functionality can be used, but this approach requires that the desired products be acid or base stable (or both) and limits the functionality that can be present.
Recently, fluorous synthetic and separation techniques have attracted the interests of organic chemists. In fluorous synthetic techniques, reaction components are typically attached to fluorous groups such as perfluoroalkyl groups to facilitate the separation of products. Reactions are carried out in the solution phase, so solubility and reaction problems inherent with solid phase synthetic techniques do not arise. In general, fluorous tagged or scavenged molecules partition preferentially into a fluorous phase while non-tagged/non-scavenged molecules partition into an organic phase. Although fluorous synthetic and/or separation techniques are promising, such techniques are currently limited by a lack of available and suitable fluorous tags and scavengers.
Accordingly, further improvements would be a welcome addition to the art, wherein fluorous tagging and scavenging compounds, and methods for their synthesis and use in increasing the fluorous nature of organic compounds are developed.